Intellia Therapeutics - Q3 2024

Executive Summary

• Q3 2024 collaboration revenue was $9.11M and net loss per share was $(1.34); revenue declined year over year (Q3’23: $11.99M) but improved sequentially (Q2’24: $6.96M), while EPS improved sequentially vs Q2’24 $(1.52).
• Cash, cash equivalents and marketable securities were $944.7M at September 30, 2024; management reiterated funding runway into late 2026.
• Execution catalysts: HAELO Phase 3 for NTLA‑2002 initiated with active screening; FDA cleared IND for MAGNITUDE‑2 Phase 3 in ATTRv‑PN; MAGNITUDE Phase 3 (ATTR‑CM) enrollment tracking ahead, now at 60+ sites and >20 countries.
• New clinical data updates flagged: AHA late‑breaking oral for NTLA‑2001 Phase 1 (ATTR‑CM) on Nov 16 (biomarkers and functional capacity); NTLA‑2002 Phase 2 detailed results published in NEJM and presented at ACAAI with majority attack‑free at 50 mg dose.

What Went Well and What Went Wrong

What Went Well

• Rapid Phase 3 execution: HAELO (NTLA‑2002) initiated with 2:1 randomization and crossover design; enrollment expected to proceed rapidly based on strong patient/investigator enthusiasm.
• Regulatory de‑risking: FDA cleared IND for MAGNITUDE‑2 (ATTRv‑PN) enabling a small placebo‑controlled ex‑U.S. Phase 3 trial; study designed with mNIS+7 at 18 months and serum TTR at day 29.
• Efficacy signals: NTLA‑2002 Phase 2 showed 77–81% mean attack rate reduction and 8/11 patients in 50 mg arm attack‑free through latest follow‑up; kallikrein reduction 86% at 50 mg; safety profile favorable.
  • Quote (CEO): “A one‑time treatment of NTLA‑2002 has the potential to be a functional cure”.

What Went Wrong

• Top‑line financial pressure: Collaboration revenue declined YoY ($9.11M vs $11.99M) and net loss widened YoY ($135.7M vs $122.2M) driven by higher R&D to advance lead programs; revenue softness tied to AvenCell collaboration reduction.
• Expense growth: R&D expenses increased to $123.4M from $113.7M YoY; G&A ticked up to $30.5M (vs $29.4M) with higher stock‑based comp.
• Fair value mark‑to‑market headwind: Q3 reflected $(3.06)M change in fair value of investments (other income line), partly offsetting interest income.

Transcript

Operator (participant)

Good morning and welcome to Intellia Therapeutics' third quarter 2024 financial results conference call. My name is Drew, and I will be your conference operator today. Following formal remarks, we will open the call up for a question-and-answer session. This conference is being recorded at the company's request and will be available on the company's website following the end of the call. As a reminder, all participants are currently in listen-only mode. If anyone requires operator assistance during the conference, please press star zero on your telephone keypad. I will now turn the conference over to Lina Li, Senior Director of Investor Relations and Corporate Communications at Intellia. Please proceed.

Lina Li (Senior Director of Investor Relations, and Corporate Communications)

Thank you, Operator, and good morning, everyone. Welcome to Intellia Therapeutics' third quarter 2024 earnings call. Earlier this morning, Intellia issued a press release outlining the company's progress this quarter, as well as topics for discussion in today's call. This release can be found on the Investors and Media section of Intellia's website at intelliatx.com. This call is being broadcast live, and a replay will be archived on the company's website. At this time, I would like to take a minute to remind listeners that during this call, Intellia management may make certain forward-looking statements and ask that you refer to our SEC filings available at sec.gov for the discussion of potential risks and uncertainty. All information presented on this call is current as of today, and Intellia undertakes no duty to update this information unless required by law.

Joining me from Intellia are John Leonard, Chief Executive Officer, David Lebwohl, Chief Medical Officer, Laura Sepp-Lorenzino, Chief Scientific Officer, and Ed Dulac, Chief Financial Officer. John will begin with recent business highlights. David will provide updates on our clinical pipeline progress. Laura will then provide R&D updates, and Ed will review our financials before we open the call for questions. With that, I will now turn the call over to John, our Chief Executive Officer.

John Leonard (CEO)

Thank you, Lina. Good morning, everyone, and thank you all for joining us today. At Intellia, we are ushering in a new era of medicine. During the third quarter and more recent period, we have made substantial progress in our efforts to bring promising, highly differentiated, and potentially curative CRISPR-based gene editing treatments to patients. In October, at the American College of Allergy, Asthma, and Immunology Annual Scientific Meeting, we presented unprecedented positive results from our phase two study of NTLA-2002 for the treatment of hereditary angioedema. These results showed that a simple one-time infusion of NTLA-2002 offers patients the potential for a functional cure. For people living with HAE, current treatment options are limited to chronically administered prophylactic therapies to prevent or manage attacks and the use of on-demand therapy to control breakthrough attacks. Because of this, available therapies place emphasis on attack rate reductions for their lifelong treatments.

However, our market research is clear: patients want to lead a normal life, one that is free of attacks, free of chronic treatment, and free of mental burden around potential triggers and the loss of access to their therapies. The emerging profile for NTLA-2002 provides hope that a single intervention may lead to the complete elimination of angioedema attacks and remove the need for subsequent prophylaxis therapy for most patients. The opportunity to deliver such a profile will create significant value for patients and the healthcare system as a whole. We're extremely encouraged by our phase two results, and we're actively screening patients in Phase 3 HALO study. The strong enthusiasm for NTLA-2002 from patients and our investigators strengthens our conviction that Phase 3 will enroll rapidly, enabling us to submit a planned BLA in 2026. In addition, we're making excellent progress across our other late-stage trials.

As announced this morning, the FDA cleared our IND application for MAGNITUDE-2, Phase 3 trial of Nex-Z for patients with hereditary ATTR amyloidosis with polyneuropathy. We expect to initiate the study in the coming days. Since dosing our first cardiomyopathy patient in March, we continue to see strong momentum in Phase 3 MAGNITUDE study, and enrollment is tracking ahead of our internal projections. With three Phase 3 studies expected by year-end, we are leading the field of in vivo CRISPR-based medicines. Intellia is ushering in a new era of medicine with the prospect of a functional cure for patients suffering from HAE and a treatment that may change the course of the disease for people with ATTR amyloidosis. I'll now hand the call over to our Chief Medical Officer, David Lebwohl, who will provide an update on our clinical programs. David.

David Lebwohl (Chief Medical Officer)

Thanks, John. I'll begin with 2002 in development for hereditary angioedema, or HAE. As John noted, we presented phase two data, which demonstrated that a single dose of 2002 could both eliminate attacks and eliminate the need for further treatment. In the 50-milligram arm, eight of 11 patients had no attacks during the 16-week primary observation period after a single dose of 2002. These groundbreaking results highlight how 2002 has the potential to reset the standard of care for HAE. We are encouraged by the findings thus far from the post-primary observation period in the phase two as well. The eight patients who are attack-free in the 50-milligram cohort remain attack-free with no HAE-directed therapy for a median of eight months so far. Moreover, the three patients who are not yet attack-free achieved clinically meaningful attack rate reductions.

Based on our phase one observations, we expect these patients to show continued improvement or become attack-free as they have more time to adjust to their new normal. We are continuing to follow all patients and look forward to presenting longer follow-up data next year. With 2002, we believe we are creating a new standard for patient outcomes in HAE, where 12 out of 15 patients, or 80% of patients who received the 50-milligram dose in the phase one-two study, appear functionally cured of their disease. That is, patients who are attack-free without the need for further treatment. This is unprecedented and suggests an emerging product profile that is unmatched by other HAE therapies, either currently approved or in development. Importantly, our market research indicates that 2002's emerging product profile aligns directly with the needs and priorities of patients and physicians.

As such, we expect broad interest and demand for 2002 that will drive rapid enrollment of Phase 3 study and commercial uptake once approved. We are now actively screening patients in the Phase 3 study, a global randomized double-blind placebo-controlled study. Importantly, Phase 3 study will extend the primary observation period and look at the number of HAE attacks from weeks 5 through 28 as its primary endpoint. This is designed to provide a cleaner read into the drug's effects once kallikrein reduction has reached its steady state about a month after therapy. As previously guided, we expect to submit a BLA filing in 2026 from the 60-patient study. In summary, we believe 2002 is well-positioned to be the first approved in vivo CRISPR gene editing treatment and a truly transformative one-time treatment for people living with HAE.

Switching to Nex-Z, also known as NTLA-2001, in development for the treatment of ATTR amyloidosis. This multi-system disease primarily manifests as either cardiomyopathy due to amyloid deposits in the heart or polyneuropathy through the progressive accumulation of protein deposits in the nervous system. We announced today that the U.S. FDA cleared our IND application to initiate Phase 3 trial in patients with hereditary ATTR amyloidosis with polyneuropathy. This marks our fourth consecutive IND clearance within 30 days of submission for in vivo therapies we have developed, an unparalleled regulatory track record in the field of gene editing, and testament to our high standard for drug development. Our Phase 3 trial is an international randomized double-blind placebo-controlled study. 50 patients will be enrolled and randomized one-to-one to receive a single 55 mg infusion of Nex-Z or placebo.

Patients randomized to the placebo arm will be eligible for optional crossover to receive Nex-Z. The primary endpoints are the change from baseline in mNIS+7 at month 18 and serum TTR at day 29. In polyneuropathy, there is a positive correlation between greater TTR protein reduction and improved clinical benefit. To date, no other agent approved or in clinical development has demonstrated consistent, deep, and durable TTR reduction like Nex-Z, which gives us tremendous confidence in our ability to positively impact patient outcomes in the MAGNITUDE-2 study. We expect to initiate the study at ex-US sites in the coming days. Simultaneously, the rapid enrollment of the MAGNITUDE trial in patients with cardiomyopathy continues to track ahead of our internal projections based on strong patient and physician interest.

In total, we are actively enrolling patients at over 60 sites and have received regulatory clearance in more than 20 countries for Phase 3 study. Findings in a recent publication of a competitor's clinical data in ATTR-CM indicate that there is a major opportunity to improve patients' clinical outcomes beyond what current therapies provide. In our ongoing phase one study, we demonstrated that all patients with cardiomyopathy achieved rapid, deep, and durable TTR reduction with Nex-Z, more consistent and greater mean reductions than that reported with TTR silencers. As such, our early clinical data suggests Nex-Z could significantly reduce total TTR exposures, which in turn might provide greater clinical benefit for patients. Next Saturday, November 16th, we will be presenting new findings from the ongoing phase one study as a late-breaking oral presentation at the American Heart Association Scientific Sessions.

On the occasion of AHA's 100th anniversary, we will be presenting data at the opening session titled "Celebrating a Century of Cardiovascular Science: From Prevention to Treatment to Cure." These data will provide insights into the emerging clinical profile of Nex-Z and the hypothesis that greater TTR reduction leads to better clinical outcomes. The update will include data from all 36 patients within the cardiomyopathy arm, including important measures of clinical and functional benefit. This includes safety, reduction of TTR, and disease progression markers such as NT-proBNP, troponin, and 6-minute walk test at month 12 compared to baseline. We look forward to reviewing these data on an investor webcast taking place that same day, where we will also provide an update on the polyneuropathy arm. I'll now hand the call over to Laura, our Chief Scientific Officer, who will provide updates on the 3001 program and our R&D efforts.

Laura Sepp-Lorenzino (Chief Scientific Officer)

Thank you, David. Good morning, everyone. We're advancing our science beyond in vivo knockout therapies and into our first in vivo gene insertion programs in the clinic. NTLA-3001 is our first wholly owned in vivo gene insertion program for alpha-1 antitrypsin deficiency-associated lung disease. It is designed to precisely insert the wild-type SERPINA1 gene, which encodes the alpha-1 antitrypsin protein. In previously presented non-human primate data, we've demonstrated the ability to produce fully functional alpha-1 protein at normal levels after a single dose. Notably, these normal levels of alpha-1 protein were durable through two years of follow-up in the completed study. We're on track to dose the first patient in the phase one-two study of NTLA-3001 by year-end.

If we're able to translate what we have seen in non-human primates to humans, we believe this will be a major step forward for alpha-1 patients and the field of gene editing. Assuming success, it would unlock a whole new category of diseases which require a gain of function that we could pursue with our modular insertion platform. In parallel, we're continuing to advance our toolbox of novel gene editing and delivery technologies to extend the reach of CRISPR-based gene editing for in vivo and ex vivo therapeutic applications. This includes advancing gene editing programs in five different tissues outside the liver, either independently or in collaboration with partners. We're proud of all the recent progress and look forward to providing more updates as we advance our platform and pipeline.

I'll now hand over the call to Ed, our Chief Financial Officer, who will provide an update on our financial results as of third quarter 2024.

Edward Dulac (CFO)

Thank you, Laura, and good morning, everyone. Intellia continues to maintain a solid balance sheet that allows us to execute on our pipeline and platform. Our cash, cash equivalent, and marketable securities were approximately $944.7 million as of September 30, 2024, compared to $1 billion as of December 31, 2023. The decrease was driven by cash used to fund operations of approximately $335 million. The decrease was offset in part by $176.9 million of net equity proceeds from the company's aftermarket program, $47 million of collaborator reimbursements, including a one-time $30 million payment received in April related to the company's technology collaboration with Regeneron, $37.2 million of interest income, and $6.5 million in proceeds from employee-based stock plans. Our collaboration revenue was $9.1 million during the third quarter of 2024, compared to $12 million during the third quarter of 2023.

The $2.9 million decrease was mainly driven by a reduction in revenue related to the AvenCell license and collaboration agreement. R&D expenses were $123.4 million during the third quarter of 2024, compared to $113.7 million during the third quarter of 2023. The $9.7 million increase was primarily driven by the advancement of our lead programs. Stock-based compensation included in R&D expense was $24.2 million for the third quarter. G&A expenses were $30.5 million during the third quarter of 2024, compared to $29.4 million during the third quarter of 2023. The $1 million increase was primarily related to stock-based compensation. Stock-based compensation included within G&A expense was $15.4 million for the third quarter of 2024. Finally, we expect our cash balance to fund our operating plans into late 2026.

John Leonard (CEO)

Thanks, Ed. In conclusion, Intellia continues to deliver on the promise of gene editing, and we look forward to presenting the Nex-Z phase one update next week at AHA. With that, we will now open the call for your questions. To do our best to address as many questions as possible, we will only be able to take one question per caller. Operator, you may now open the call for Q&A.

Operator (participant)

We will now begin the question and answer session. To ask a question, you may press star then one on your touch-tone phone. If you're using a speakerphone, please limit your handset. Excuse me, please pick up your handset before pressing the keys. To withdraw your question, please press star then two. Please limit yourself to one question. At this time, we will pause momentarily to assemble our roster. The first question comes from Rick Bienkowski with Cantor Fitzgerald. Please go ahead.

Rick Bienkowski (Analyst)

Hey, good morning, and thank you for taking the question. I was just hoping to get more color on the pace of enrollment into MAGNITUDE-1. Just looking at the clinical trial record on ClinicalTrials.gov, the estimated primary completion is listed at December 2027. So could you just walk me through the assumptions there for the pace of enrollment, given that the primary endpoint is event-driven?

John Leonard (CEO)

Thanks for the question, Rick. As we've said, you can use the HELIOS study as a good proxy with similar assumptions. You know that the study has 765 patients. We have global sites activated, and the final sites are being activated as we speak here. So as we said in our comments here, we're enrolling ahead of our projections, and as we get further insight, there may be an opportunity to update that down the road, but in the meanwhile, things are progressing very, very well.

Operator (participant)

The next question comes from Alec Stranahan with Bank of America. Please go ahead.

Alec Stranahan (Senior Analyst in Equity Research)

Hey, guys. This is Matthew on for Alec. Thanks for taking our question. Just one quick one for us. As you think about extending into later-stage clinical trials, just thinking about your capital allocation priorities, given you have a lot going on in the pipeline and sort of how you're thinking about in vivo versus ex vivo going forward.

John Leonard (CEO)

So maybe Ed can address that, and we'll follow up as necessary.

Edward Dulac (CFO)

Yeah, thanks for the question. I mean, we exited the third quarter with about $945 million in cash. And as we look at our two or three-year plan, I think we've laid out at JPMorgan earlier this year three-year priorities, strategic priorities through 2026. And so as I look at the company today, we clearly have a focus on the Phase 3 studies, which will be up and running before the end of the year. And that's clearly a focus. We do have some exciting programs related to 3001, our first gene insertion program, which is an important proof of concept for us, as well as sort of burgeoning ex vivo opportunities as well. And then we've been very prominent in just investing across the platform. So I look at our existing cash burn at roughly $100 million over the last couple of quarters.

It's a reasonable estimate that should go up, but I feel like we have a very conservative plan in place, one that takes our existing cash balance and gets us well into fourth quarter of 2026.

Operator (participant)

The next question comes from Yanan Zhu with Wells Fargo Securities. Please go ahead.

Yanan Zhu (Senior Equity Research Analyst)

Great. Thanks for taking our questions. First, congrats on the clearance from FDA to conduct Phase 3 study in ATTR polyneuropathy. I was just struck by two things from the trial design. One is that it is a placebo-controlled study and not silencer, for example, active arm controlled study. And the other is that the patient—the study size is very small, 50 patients. That's not even half of the size of the silencer studies. So could you comment on the ability to obtain such a study design? What does it mean? And also, will patients on either arm allowed to receive silencer or other active treatment during the study? Thank you.

John Leonard (CEO)

Thanks for the question, Yanan. First of all, it's important to note that the effect size of TTR reduction is very, very large in patients with polyneuropathy. That's been established. We have pretty good insight as to the effects as a function of TTR reduction. And as we've shared elsewhere, our TTR reduction is profound, and we expect that to continue into this patient population Phase 3. A placebo-controlled trial is possible based on our agreement with the FDA and other regulatory agents. It will give us a very solid readout on the performance and safety of the drug. And by carrying it out outside the United States, where many of these other therapies are not currently available, it allows the study to be enrolled promptly and we'll be in a position to share the data when we have it.

David, you can speak to any other details that you think are pertinent to that study or silencers.

David Lebwohl (Chief Medical Officer)

Yeah, thank you, John. I think what you're seeing in this small study is a great collaboration with the FDA as we talk to them about the best way to go forward. All the other drugs have been approved with placebo-controlled studies, so that makes a lot of sense as well for our drug. And again, silencers are not available in the country where the studies are being conducted, so patients will not be receiving silencers.

Yanan Zhu (Senior Equity Research Analyst)

Got it. Thank you.

Operator (participant)

The next question comes from Mani Foroohar with Leerink. Please go ahead.

Alec Stranahan (Senior Analyst in Equity Research)

Hi, good morning. This is CJ on for Mani. My question is regarding Phase 3 HALO study. I just noticed that patients are randomized two to one there versus one to one in MAGNITUDE. So I was just wondering if you thought this two to one enrollment was thought to accelerate patient enrollment in the study. Thank you.

John Leonard (CEO)

David, do you want to speak to the randomization scheme?

David Lebwohl (Chief Medical Officer)

Yeah, the benefit of a two to one randomization is for the patients themselves. It's attractive to them that they'll have two-thirds chance to start on the active drug right away. All these patients will be able to cross over if they wish as well at the end of the primary observation period. So it's also attractive to patients for that reason. With all that in place, we do anticipate very rapid enrollment as we saw in the phase two as well. The number of patients, by having two to one also, you have more information on the active arm as part of the BLA submission that'll be coming up in 2026.

Operator (participant)

The next question comes from Kostas Biliouris with BMO Capital Markets. Please go ahead.

Kostas Biliouris (Analyst)

Good morning, everyone. Thanks for taking our question and congrats on the progress. One question from us on the AATD program. Given that the gene that you inserted isn't under the control of the natural promoter, and during infection, patients need about two to three times more AAT protein, can you remind us how do you ensure that this additional AAT protein is there during infections? Thank you.

John Leonard (CEO)

Thanks for the question, Kostas. We base our excitement over the Alpha-1 program on the preclinical lab, where, as you point out, the natural transgene is driven by the albumin promoter, and with that and non-human primates, we've achieved normal levels of the protein. I would not expect that to be the typical response to infection because it will be driven by the albumin promoter, but what we've prioritized is normalizing the protein because it's the primary defect in patients with the disease, and we think that that's going to be the primary determinant of the success of the product.

Operator (participant)

The next question comes from Joseph Thome with TD Cowen. Please go ahead.

Joseph Thome (Managing Director, and Senior Research Analyst)

Hi there. Good morning. Congrats on the progress, and thank you for taking my question. Maybe just on the MAGNITUDE-2 study, as the serum TTR reduction is going to be a day 29 read, and the mNIS+7 is 18 months. Are you able to take a look at serum TTR ahead of that 18-month time point while maintaining some sort of blind, or should we anticipate both of those readouts coming at once? And then secondly, on a submission for PN, how much does the submission in PN depend on also success in MAGNITUDE for CM, or are these completely uncoupled? Thank you.

John Leonard (CEO)

Maybe I can address that, and David can fill in blanks. The two programs, polyneuropathy and cardiomyopathy, are independent of each other, and they're determined by the study designs in each of those particular indications. We've talked earlier on the call here about the cardiomyopathy program and how to think about that. Polyneuropathy program, as was pointed out, will have an 18-month observation period that's set in time, sort of a landmark design. But the two are independent of each other. We would expect that safety will be supplementary from each of the programs as data accumulates, but in terms of the efficacy read, they're entirely independent. The study is blinded, and we will not be in a position where we'll be sharing data prematurely before the complete data readout. So don't look for TTR and then the ultimate clinical outcomes.

It will be the full set of data as it becomes available. David, if you have anything to add to that, be my guest.

David Lebwohl (Chief Medical Officer)

I'll just add to the observation that you've seen in our data that all patients have a major reduction in TTR. So though we won't be looking at that data, what we know from our experience is that all patients will be able to achieve a rapid and deep reduction in TTR, and that that is maintained probably permanently as far as we know, but certainly over two years at this point. So we will see that at the time of unblinding, as John says, and we pretty much know what to expect in that data.

Operator (participant)

Thank you. The next question comes from Gena Wang with Barclays. Please go ahead.

Antonio Castanon (Analyst)

Hi, it's Tony on for Gena. So on ATTR, can you remind us of your assumptions for silencer drop-in rate and any strategies to address this if it ends up being higher than expected?

John Leonard (CEO)

David, do you want to speak to the silencer drop-in rate?

David Lebwohl (Chief Medical Officer)

Yeah. We have figured that into our trial. We haven't given the exact way that will happen. We should mention we think it's less likely now that we've seen the Helios data that there will be much drop-in. What we've seen is that there is some addition to TTR to the tafamidis in that trial, but probably not enough to justify payers to pay for both drugs together. So what we expect to see is that patients will continue on their tafamidis in our study. They possibly may switch to vutrisiran if payers allow that. But even that switch, we don't think will have any effect on our primary endpoint.

Operator (participant)

Got it. Thank you. The next question comes from Maury Raycroft with Jefferies. Please go ahead.

Maury Raycroft (Analyst)

Hi, good morning. Congrats on the progress, and thanks for taking my question. I was wondering if you could just talk more about how you're setting expectations for the AHA update for biomarkers and the relationship or correlation to functional capacity. I'm wondering if you'll show individual patient data, potentially cardiac remodeling or imaging data as well?

John Leonard (CEO)

I think I can start with that question, and David can fill in some additional information. As we said in our comments, we're very enthusiastic about sharing the data at the upcoming AHA meeting, and we're honored to be featured in the opening session of the meeting, which is something that is addressing the next century of cardiac therapies. We're very excited to be a part of that. As we've long said, we'll share biomarker data, functional data, and clinical information on these patients. And in terms of how we think about that, the meaning of that information, first, we're excited about what we see because it relates for the first time to the extent of the TTR reduction that we're achieving with those particular readouts.

We think it will yield real insights into how we think about the MAGNITUDE study and how we expect the drug to perform in that particular study. David, if you want to share any other comments.

David Lebwohl (Chief Medical Officer)

Yeah, just to add, you'll see the data on November 16th. Recall that in the Phase 3s, the active arms continue to show worsening in terms of these biomarkers. NT-proBNP continues to rise. 6-minute walk continues to go down. Even though they're better than placebo, they are still worsening in the populations as a whole. So it's important to observe as you see our data. Our data is also a very robust test of the ability of deep TTR reductions to make a big clinical difference. And that's because 50% of our patients are Class III instead of the 10% or so you see in the other studies. And a full 31% of the patients have variant disease, which is really the very aggressive disease in ATTR-CM. And those patients as well in the other studies in around 10%-12%.

You will be seeing all 36 patients in the study because they've all reached one year, and you will see the data for these patients comparing baseline to one year.

Operator (participant)

Got it. Thanks for taking my question. The next question comes from Ry with Guggenheim. Please go ahead.

Mandeep Rai (Analyst)

Hi, this is Ry from Debjit's team. What factors do you think are the major contributors to enrollment being ahead of schedule in the MAGNITUDE ATTRCM study? And do you think these factors apply to MAGNITUDE-2 for PN?

John Leonard (CEO)

What investigators tell us is they've been extremely excited with the extent of the TTR reduction and the safety profile that they've seen with the drug to this date. We've seen confirmation with competitor programs that lowering TTR is meaningful for patients. And the deep, consistent, and enduring reductions that we've achieved with the drug thus far, I think, has really excited treating physicians around the world. We would anticipate that this will apply also to the MAGNITUDE study. And recall that in many of these countries, this kind of therapy is not available for patients, generally speaking. And we know that there's great enthusiasm with all the sites that we've spoken to.

Operator (participant)

The next question comes from Dae Gon Ha with Stifel. Please go ahead.

Dae Gon Ha (Director, and Equity Research Analyst)

Hey, great. Good morning. Thanks for taking our questions and congrats on the progress. Question on AATD, just thinking about the phase one that's going to embark by the end of the year, if you can comment on any flexibility in that trial protocol to include any liver disease patients. I know that was supposed to be more of a 2003 purview, but given the biology and the potential, say, facilitation of polymer excretion from the cells once you have more M protein, just wondering if you can add in a little bit of that sentinel cohort, if you will, just to see the benefit there. Thanks so much.

John Leonard (CEO)

David, any prospects for including liver disease in the 31 trial?

David Lebwohl (Chief Medical Officer)

Yeah, these patients will not be having any kind of major liver disease. Those patients with liver disease really are best addressed by reducing the mutant protein, as well as, of course, giving the increased alpha-1 antitrypsin would be valuable to them as well. But without our ability to reduce the Z protein, we don't think we're doing them full justice.

Operator (participant)

The next question.

John Leonard (CEO)

Just to add, recall that we're taking an extended approach to going after alpha-1 and in addition to 3001, which we think will teach us a lot about the insertion approach for alpha-1 disease and leads to a multiplicity of other diseases for which insertion may be the path forward. We're also bringing forward a gene-writing program that would address not only the lung but also the liver.

Operator (participant)

Okay. The next question comes from Luca Issi with RBC. Please go ahead.

Luca Issi (Senior Biotechnology Research Analyst)

Oh, great. Thanks so much for taking our question. This is Lisa on for Luca. Congrats on all the progress here, team, and getting the IND cleared for TTR polyneuropathy. Just one question on the study. I know the primary endpoint is mNIS+7 at 18 months. However, I believe Alnylam was able to file on just nine months of follow-up. So I'm just curious if the 18-month endpoint was mostly needed to satisfy European regulators, or did the FDA also request the longer follow-up? Any color here would be helpful. Thanks so much.

John Leonard (CEO)

David, any comments to share on 18 months versus a different follow-up time?

David Lebwohl (Chief Medical Officer)

Yeah, we felt 18 months was looking at the trials. We felt 18 months was the optimal time to really see the full benefit of the drug. It was not required by regulators, but it was really our own decision to do that.

Operator (participant)

The next question comes from Salveen Richter with Goldman Sachs. Please go ahead.

Salveen Richter (Analyst)

Hi, this is Mark on for Salveen. First, congrats on the quarter, and thank you for taking our questions. The recently presented phase two data from NTLA-2002 and HAE, can you discuss the data in the context of read-through to the recently Phase 3 HALO study and any takeaways that you're applying to HALO?

John Leonard (CEO)

Thanks for the question. I think it's really important to step back and consider what we've actually presented for 2002 thus far. If you take the 50-milligram doses from both the phase one and phase two studies, we've reported on 12 of 15 patients who have achieved what we're considering a functional cure. That means patients following a single dose and no other therapy thereafter have no attacks. That is unique in space. It's a new category of response. It is achieved, to our knowledge, only with 2002 and this class of drugs. We expect that similar outstanding results will come from Phase 3 trial. The study design is similar, with the exception that we have an even longer follow-up period to see further insights into how patients respond with even a longer observation period.

What we've seen in our phase one study is that while many patients get to a functional cure fairly quickly, there are some patients that reach that only with some additional time. So we expect that we'll have very favorable results in Phase 3 program and look forward to sharing that as we go forward.

Operator (participant)

Thank you. The next question comes from Miles Minter with William Blair. Please go ahead.

Miles Minter (Senior Research Analyst)

Hi, team. This is John on for Miles. Thanks so much for taking our question. So for 3001, I was just wondering if you could give us any idea of how many patients you are looking to dose before reporting initial data, and what kind of target are you looking for for serum AAT levels in those lower dose cohorts? Thanks.

John Leonard (CEO)

Thanks for the question. We've had a principle that we've applied since the outset with all of the clinical work that we've done here, which is that we report data when it's meaningful, consistent, and interpretable, and we'll apply that same standard here. Obviously, we're looking for a biomarker here, which is readily measured, and that's the production of the native protein, wild type, and we've said from the outset that our objective here is to normalize the levels of that protein, and that will be the basis for determining the success of the project.

Operator (participant)

Thank you. The next question comes from Joon Lee with Truist Securities. Please go ahead.

Joon Lee (Managing Director, and Senior Biotech Analyst)

Hi, good morning. This is Mehdi on for Joon, and thanks for taking our question. Given your great progress for in vivo programs that you have, any color on your future plans for using gene-writing technology is really appreciated. For example, do you plan to use it for in vivo, or this is more for your ex vivo programs?

John Leonard (CEO)

Thanks for the question. It really goes to the heart of the strategy of the company, where it's a three-pronged approach. We start with a platform that has a complete set of tools, not only on the editing side but also on the delivery side, so that as we look at any particular editing problem, we're in a position to choose what we think will be the best tool for the particular problem. And we apply those tools in both the in vivo and the ex vivo setting. We think that there are conditions for which gene-writing is well-suited. I don't think that's universally true. We think that there are certain instances, especially in the ex vivo setting, where base editing is useful or one is going to multiplex.

Then, of course, as we've shown with our Phase 3 programs, our typical CRISPR, as exemplified by 2001 and 2002, has profoundly successful results in terms of achieving the editing objectives that we're going after. In short, we'll look at the particular programs and the editing that they need and apply the gene-writing to that. One of the places where we think it's well-suited is as an adjunct to our alpha-1 program, and that would be the first place where I would expect to see it.

Joon Lee (Managing Director, and Senior Biotech Analyst)

Thank you.

Operator (participant)

The next question comes from Jay Olson with Oppenheimer. Please go ahead.

Jay Olson (Managing Director, and Senior Analyst Covering Biotechnology)

Oh, hey, congrats on all the progress, and thank you for taking the question. How are you thinking about the ex-U.S. opportunity and strategy for 2002? Are you interested in partnering the program, ex-U.S.? Thank you.

John Leonard (CEO)

Thanks for the question. Behind that is the assumption that there's a substantial commercial opportunity around the world, certainly in the developed markets. We see that starting in the U.S. and going beyond the U.S. into Europe and perhaps beyond that. Our current plans are to be in a position to launch the drug ourselves. As we evaluate partnerships, we consider what they can bring to the table to extend our own reach. As appropriate, as we learn more about that, we would share that strategy as we go forward.

Jay Olson (Managing Director, and Senior Analyst Covering Biotechnology)

Great. Thank you so much.

Operator (participant)

The next question comes from Brian Cheng with JPMorgan. Please go ahead.

Brian Cheng (Analyst)

Hi, good morning. Thanks for taking our question this morning. This is Sean on for Brian. Just speaking on the AATD program, just curious about your thoughts on the back of some of the RNA editing data from your peers. How do you view 3001's differentiation versus theirs?

John Leonard (CEO)

Thanks for the question. As we've said elsewhere, we think the key determinant of success for the pulmonary pathology of the disease will be achieving high, essentially normal levels of wild-type protein. Thus far, we are the only company that we're aware of that's presented that in the setting of a non-human primate. That is what we're looking for in our phase one study to determine whether or not we achieve those same similar proteins in humans. Obviously, we'll watch the space. There are competitive programs playing out, but it's very, very early. We'll see how successful people are at even delivering their technologies and then their performance of production of the normal protein over time.

Brian Cheng (Analyst)

Thank you.

Operator (participant)

The next question comes from Silvan Tuerkcan with Citizens JMP. Please go ahead.

Silvan Tuerkcan (Analyst)

Hey, good morning, and congrats on the progress, and thanks for taking my question. Just a quick one, and I may have missed this, but for MAGNITUDE-2, congrats on the IND, but when do we plan initiation in the US here for this trial, and what is the eventual split of patients enrolled in this trial considering US versus XUS? Thank you so much.

John Leonard (CEO)

Thanks for the question. We've tried to make it clear elsewhere that the study will be done outside the United States. It's there where one can readily conduct a placebo-controlled trial. Standards of care otherwise for these patients are similar around the world. We've worked on developing this protocol with the Food and Drug Administration in the United States, and they will accept the program coming from patients that are studied outside the United States.

Silvan Tuerkcan (Analyst)

Great. Thank you.

Operator (participant)

The next question comes from William Pickering with Bernstein. Please go ahead.

William Pickering (Senior Analyst)

Hi, good morning. Thank you for taking my question. For the AATD program, do you have any plans to expand this study beyond the New Zealand site, and is it a reasonable base case that we would see data in 2025? Thank you.

John Leonard (CEO)

David, do you want to speak to any other sites besides New Zealand?

David Lebwohl (Chief Medical Officer)

Yeah, we will be having other sites, and we'll put them on clinicaltrials.gov as they come up. I should say it is possible that we'll have data. Reasonable to think we have data in 2025.

Operator (participant)

The next question comes from Andy Chen with Wolfe Research. Please go ahead.

Andy Chen (Analyst)

Hi, Brendan on for Andy. So we know docs are excited about your ATTR therapy, but can you please compare the excitement relative to their excitement for stabilizers and silencers? So let's say you achieve similar efficacy on endpoints based on feedback now. Are docs much more likely to use gene editing compared to a silencer, for example? Any safety concerns about using gene editing in a very old population? Thank you.

John Leonard (CEO)

David's on the front line talking to investigators. Can you speak to the enthusiasm for the investigators that we work with, who, by the way, many of them have worked with silencers already, so they are in a position to be thinking about both those compounds?

David Lebwohl (Chief Medical Officer)

Yeah, thanks, John. I think you've heard our hypothesis for a number of years that deeper reductions in TTR will lead to better results. Our drug is also more rapid in getting down to low levels than silencers, as well as getting to those deeper levels. And it is continuous, so the levels are staying continuously low instead of what might happen if you give infusions of drugs periodically. So based on that, that excitement about the low levels we're achieving, we have heard a lot of excitement from physicians thinking this could be better than silencers. That is something we want to prove Phase 3, but that's what we hear from investigators, and that's why we think it's enrolling quite briskly. There haven't been any safety concerns raised in an elderly population.

We've seen it well tolerated in all the patients, including Class III patients and some very sick patients, and all the patients were able to receive a full dose of the drug as part of their therapy in the trial.

John Leonard (CEO)

Maybe something to add is that we now have over three years of follow-up in our earliest dose patients, and the excellent safety profile that we reported in the early days has continued. We think many of the questions that surrounded gene editing are being addressed as these programs enroll. I think another thing to keep in mind with respect to patients who are older, which typifies the wild-type patient population, these patients live for a long time. And you can look at the recently reported results and see that there's high levels of survival years after the patients have been dosed. And I think that speaks importantly to the role of these agents, what they can do for these patients, the evolving care of them, and ultimately a pharmacoeconomic argument for treating patients like this who should derive the full benefit of the therapy.

One other thing with respect to older patients, it's common to think of TTR cardiomyopathy as a heritable disease. In fact, in most cases, it's a disease of aging. 90-plus% of the patients who suffer from the disease have wild-type protein. And you can see that in Phase 3 trials that have been reported. So unfortunately, we're making many more of these patients annually as the population ages. And so it's not correct to think about it as a typical sort of genetic disease.

Operator (participant)

The next question comes from Whitney Ijem with Canaccord Genuity. Please go ahead.

Whitney Ijem (Managing Director)

Hi, good morning, and thanks for taking our question. This is Joanne on for Whitney. Just trying to understand the rationale for the 2001 polyneuropathy IND, given Phase 3 will be run ex-U.S. Any color you can provide on that? Just want to make sure we're not missing any nuance here. Thank you.

John Leonard (CEO)

Why do we have an IND and do the study outside the United States?

David Lebwohl (Chief Medical Officer)

Yeah. The reason is that when you plan a BLA in the United States, it's a good idea to get agreement with the FDA on the design of that study. And that's what we've obtained with this IND. They agreed to the study you're seeing presented today, and this will go forward to a BLA in the U.S. as well as around the world.

Operator (participant)

This concludes our question-and-answer session. I would like to turn the conference back over to Lina Li, for any closing remarks.

Lina Li (Senior Director of Investor Relations, and Corporate Communications)

Thanks, Drew, and thanks everyone for your questions today. We appreciate all of your continued support and look forward to connecting with everyone again after the AHA presentation on Saturday, November 16th. Have a great day.

Operator (participant)

The conference has concluded. Thank you for attending. You may now disconnect your line.